Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells

Abstract

Angiogenesis is a key event in tumor progression and metastasis. This complex process, which constitutes a potent target for cancer therapy, is inhibited by very low concentrations of microtubule-targeting drugs (MTD). However, the intimate mechanisms of the antiangiogenic activity of MTDs remain unclear. Recently, we have shown that low antiangiogenic and noncytotoxic concentrations of paclitaxel induced an unexpected increase in microtubule dynamics in endothelial cells. In this study, we showed that vinflunine, the newest Vinca alkaloid, increased microtubule dynamic instability in human endothelial cells after 4-hour incubation at low concentrations (29% and 54% at 0.1 and 2 nmol/L). The growth and shortening rates were increased, and the percentage of time spent in pause and the mean duration of pauses were decreased, as previously observed with paclitaxel. As opposed to paclitaxel, the transition frequencies were not significantly disturbed by vinflunine. Moreover, low concentrations of vinflunine did not affect mitotic index and anaphase/metaphase ratio. Interestingly, these low vinflunine concentrations that increased microtubule dynamics exhibited an antiangiogenic effect through the inhibition of both morphogenesis and random motility. Capillary tube formation on Matrigel was decreased up to 44%. The cell speed and the random motility coefficient were decreased (13% and 19% and 13% and 33% at 0.1 and 2 nmol/L, respectively) and the persistent time was statistically increased. Altogether, our results confirm that the increase in microtubule dynamics is involved in MTD antiangiogenic activity and highlight the crucial role of interphase microtubule dynamics in angiogenesis. (Cancer Res 2006; 66(6): 3256-63)

ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties

“…Random cell motility was assessed by time-lapse microscopy as previously described (26). Briefly, cells were seeded on a 24-well gelatin-coated plate and allowed to adhere for 1 hour.…”

Microtubules in 3D cell motility

“…In fact, even low doses of different microtubule-targeting agents (MTAs), which were insufficient to block cell division, impaired matrix invasion by MDA-MB-231 cells (Tran et al, 2009). Microtubule requirement for pseudopod-based motility in 3D was also tested and confirmed by MTA-based approaches in endothelial cells (Lyle et al, 2012;Martins and Kolega, 2012;Pourroy et al, 2006). Nocodazole treatment also caused defects in elongation of invadopodia, which are small specialized protrusions observed in tumor cells that are thought to play a role in cancer invasion (Di Martino et al, 2016;Schoumacher et al, 2010).…”

Novel cis-restricted β-lactam combretastatin A-4 analogues display anti-vascular and anti-metastatic properties in vitro

“…As we previously reported that exposure of normal breast epithelial cells to CA-432 induced only a minimal amount of cytotoxicity with an IC 50 value of greater than 10 mM (19), it is interesting that the compounds had such a potent effect on non-cancerous endothelial cells. This phenomenon has been reported with CA-4P (38) and numerous other microtubuletargeting agents (22,39) and is postulated to be attributable to a variety of mechanisms including enhanced uptake mechanisms in endothelial cells (40) or differences in endothelial cell tubulin composition, its post-translational modifications or its microtubule-associated proteins (41,42).…”